Project summary The untreated burden of post-traumatic stress disorder (PTSD) in the United States is a massive contributor to healthcare budgets in both the military and civilian sectors, and better treatment and prevention methods are needed. Fortunately, awareness of PTSD among military service members has grown in recent years, and yet, there is a hidden epidemic of PTSD among civilians and women. Women experience PTSD at about twice the rate of men (11% vs. 5%), but the causes for this sex difference are largely unknown. It has long been suspected that sex hormones play a major role in development of ? and also potentially protection from ? PTSD and other mental health disorders. This project will provide the largest ever study of sex hormone effects on PTSD and the related mental health outcomes of depression and anxiety disorders. Whereas studies in the past were limited by small sample sizes and results were inconclusive, this investigation will use a massive sample size of approximately 500,000 participants to answer questions about two well-known sex hormones (testosterone and estradiol) and three psychiatric outcomes (PTSD, depression, and anxiety disorders). These variables were measured in the UK Biobank, and we have been granted access to the data to study sex hormone effects on mental health outcomes and to study genetic effects underlying both sex hormone levels and mental health disorders. The completion of this work will reveal whether rates of mental health disorders vary with testosterone and estradiol levels. It may be the case that levels of hormones that are both too high and too low are problematic. Given this reality, we will use sophisticated regression and machine learning techniques, and therefore we will be able to detect linear and non-linear relationships between sex hormones and PTSD, depression, and anxiety disorders. The sample size and study design make this the most powerful study conducted to date, and the results will be generalizable to diverse populations. In addition to the outcomes mentioned above, we will further explore genetic effects underlying relationships between sex hormones and mental health disorders. To do this, we will conduct genome-wide association studies (GWAS) of both testosterone and estradiol. We will then make polygenic scores for testosterone and estradiol, yielding genetic proxies of sex hormone levels which can be used in studies in which sex hormones have not been measured. Finally, we will test for shared genetic effects between genetic effects on sex hormones and genetic effects on psychiatric disorders in order to better understand the etiology of these common, debilitating, and inadequately treated mental health disorders. Taken together, these findings will provide critical foundational knowledge relevant to clinical trials which are currently testing testosterone and estradiol as treatments for PTSD, depression, and anxiety disorders. These results will also provide actionable findings for the development of novel treatment and prevention strategies.